1. Technical Field
The embodiments herein generally relate to a cancer treatment and particularly to a neutron therapy used for the treatment of cancer. The embodiments herein more particularly relate to a Boron Neutron Capture Therapy (BNCT) for the treatment of cancer and a method of synthesizing a composition for treatment of cancer based on Boron neutron capture therapy.
2. Description of the Related Art
The Neutron therapy relates to the treatment of cancer by capturing neutrons using the neutron absorbent compositions with a large neutron capture cross section. The neutron therapy is indeed a type of radiotherapy and chemotherapy methods for treating the tumors. The neutron therapy has indeed taken into account both the aspects of chemotherapy and radiotherapy. The Boron Neutron Capture Therapy (BNCT) of cancer with sustainable 10B isotope is one of the conventional methods in this field.
The BNCT depends on an interaction of the slow neutrons with enriched 10-Boron to produce the alpha particles and lithium nuclei without producing any other types of ionizing radiations. The patients are first given an intravenous injection of an enriched 10-Boron tagged chemical that preferentially binds to the tumor cells. In the clinical trials performed so far, the neutrons are created in a nuclear reactor but the particle accelerators may also be used to make the protons to collide with the targets made of Lithium or Beryllium. The neutrons pass through a moderator which shapes the neutron energy spectrum suitable for the BNCT treatment. While passing through the tissues of the patient, the neutrons are slowed by the collisions and become low energy thermal neutrons. The thermal neutrons undergo a reaction with the 10-Boron nuclei to form a compound nucleus called excited 11-Boron. The excited 11-Boron then promptly disintegrates into 7-Lithium and an alpha particle. Both the alpha particle and the Lithium ion produce closely spaced ionizations in the immediate vicinity of a reaction with a range of approximately 5-9 micrometers or roughly the thickness of one cell diameter. This technique is advantageous since the radiation damage occurs over a short range and hence the normal tissues can be spared.
FIG. 1 shows an overall schematic view of the process of the entrance of the drug and the process of Boron Neutron Capture Therapy (BNCT) used in a prior art. With respect to FIG. 1, in the method of BNCT, the drugs or compositions are generated using sustainable 10B isotope. They are then delivered to the tumor site. As the concentration of 10B reaches 20 mcg 10B/g to 35 mcg 10B/g, then the tumor can be bombarded from outside using the thermal and epithermal neutrons depending on the type and location of the tumor so that the thermal and epithermal neutrons will lead to a nuclear reaction in micro scale dimensions of the cell containing composition. This reaction generates a large amount of energy which is capable of removing the cancerous cells.
The thermal neutron is a kind of low-energy neutrons which can be produced using a reactor or an accelerator or by reducing the energy of fast neutrons generated from them through an application of proper design. This neutron bombardment generates compositions containing 10B, alpha particles having high linear heat transfer energy (LET) comprised of 4He and 7Li. The nuclear reactions occurring in the process of BNCT are shown as following:

In order to make the BNCT method to be successful, a sufficient amount of 10B should be conveyed to the tumor location selectively for receiving a sufficient amount of thermal neutrons. Due to the fact that the particles containing high-LET are only the pathways for energy transfer in the tissues, the destructive effects of these particles is therefore restricted to the cells containing 10B. As the BNCT method is more biological in comparison to the other physical treatments that use radiation, it may potentially destruct the tumor cells that are scattered in the main and healthy tissues. It is evident that the field of studies of the existing technologies towards the development of BNCT is divided into three general categories.
FIG. 2 shows a schematic block diagram indicating the components required for delivering a Boron Neutron Capture Therapy (BNCT) according to a prior art. With respect to FIG. 2, the BNCT method uses three components for providing a treatment. The first one is the drugs containing enriched 10-Boron isotope. The drug should contain sufficient amount of 10-Boron isotope. The second one is 10-boron delivery agent should have no or minimal systematic toxicity with rapid clearance from blood and normal tissues. The third one is a transfer of sufficient amount of the drug to the cancer cells in a way so that the tumor tends to absorb the targeted chemical compositions containing 10B isotope. Some other points are to be considered are the concentration ratios of drug containing enriched 10-Boron isotope into the tumor to blood and the tumor to healthy tissues (greater than 3-4:1). The fourth one is persistence of the drug containing 10-Boron isotope in the tumor for a sufficient period of time to carry out BNCT. The fifth one is a sufficient number of 10B atoms (approximately 109 atoms/cell) must be delivered selectively to the tumor (approximately 20 mcg 10B/g to 35 mcg 10B/g). The sixth one is a suitable source of thermal or epithermal neutron.
The 10B will be fissioned in or near the cancerous tumor after capturing the neutrons where the high-energy and heavy pieces resulted from the Boron fission will damage only their neighboring cells (due to dissipation of energy in low range because of the large mass of fissioned pieces) which are essentially cancerous cells (because of the absorption of targeted 10-Boron in the cancerous tissue) and as a result, the healthy tissues will get damaged minimally.
For a treatment with BNCT, the 10B isotope should be made available. The Boron compositions found in nature contain 80.1 (7)% of 11B and 19.9 (7)% of 10B. Hence the percentage of 10B has to be increased for synthesizing the active compositions in BCNT. This process of increasing 10B is called enrichment process. This kind of enriched Boron is commercially available and the different methods for separation of the isotopes from each other are also available [Annals of Nuclear Energy, 37, (2010) 1-4].
The different types of radiations are used and delivered to the cells. The different doses of radiation which are delivered to both the healthy and cancerous cells in the process of BNCT are of three types of directly ionizing radiations [Clinical Cancer Research 2005, 11(11) Jun. 1, 2005] with mutually different LET properties. These are (a) gamma rays with low LET energy which are temporarily resulted from the conversion of thermal neutrons through the hydrogen atoms of a healthy tissue [1H (n, γ)2H], (b) the protons containing high-energy LET that are produced through a rapid neutron scattering and through the conversion of thermal neutrons by the nitrogen atoms [14N (n, p) 14C] and (c) the high LET heavy particles and 7Li ions that are shot as the outcome of the conversion of the thermal neutron and fission reactions with [10B (n, α) 7Li]10B.
The higher density of ionization along the axes of the particles having high linear energy leads to an increase of biological property in comparison to a similar physical dose from a LET radiation. This process is usually called as Relative Biological Effectiveness (RBE) which is the ratio of an absorbed dose of a reference radiation source (like X-ray) to the category of test radiations that generate the same biological effectiveness. Due to the fact that there are both tumor tissues and healthy peripheral tissues in the radiation field, there will be an inevitable underlying non-specific dose which comprises the high and low LET radiations (event ideal neutron beams). However, the higher overall doses will be absorbed through high densities of 10B in tumor comparing to the adjacent normal tissues. This is the basis of BNCT in the treatment process. The overall radiation dose which is delivered to each organ can be expressed in terms of a photon equivalent unit which can be expressed as a total component of a dose with high LET multiplied with weighting factors that depends on the radiobiological effectiveness of each of the components.
Generating selectable drugs having high content of enriched 10-Boron is a significant challenge in BCNT. The produced drugs have to be nontoxic for being effective in the treatment and also it ought to have chemotherapeutic properties for destructing the cancerous cells simultaneously as well as being selective and having high content of enriched 10-Boron isotopes. In fact, the overall objective is a simultaneous application of all the influential methods for a certain and perfect destruction of cancer cells. The other significant challenge is that the produced drugs have to be accumulated sufficiently in the intended cell (20 to 35 mcg (micrograms) proportionate to the tumor gram weight). Otherwise it won't result in a sufficient impact for tumor destruction according to the US Patent 2009/0227539A1. The least accumulation ratio of tumor to blood and tumor to healthy tissue should be higher than 5 in these drugs.
Several categories have been used in BCNT. According to the U.S. Pat. No. 5,872,107 nucleotides have been used. The nucleotides, oligonucleotides containing 10B, nucleosides and oligonucleosides containing phosphorusamides containing 10B, carboranes, carbonyl pyramidine, purine have been used according to EP 1113020A2. Inorganic compounds containing Boron like borax (Na2B4O7.10H2O), sodium pentaborate (Na2B10O16.10H2O) were not very successful because their exposure to the tumor cells was not much. Also in the composition of prophyrin containing 10-Boron the ratio of tumor to the normal cell is 4 to 1. However this composition is not suitable for being used in BNCT, due to the fact that a mortality rate of mice was high due to the injection of the drug. All the other compositions applied in this regard with less successful results are monoclonal and polyclonal antibodies, encapsulating complexes like liposomes, microspheres and lipoproteins with low density according to U.S. Pat. No. 6,037,490.
Two compositions of Disodium mercapto-closo-dode-carborate (BSH) and 1-4-dihydroxyborulphenylalanine (BPA) are clinically used in the BNCT method. Although these compositions had good results regarding toxicity and impact, both the factors had medium selectability and also exhibited a low-retention time in the animal models. On the other hand, they either have low chemical residence time in terms of their structure or they have a low content of enriched 10-Boron isotopes. For instance, it was mentioned that either BSH tends to be oxidized when exposed to air or Boron has formed 5% of molecular weight of BPA. Therefore, the researches in the field of the production of compositions containing high levels of 10-Boron would not be toxic and will have aggregation and proper retention time in the cancerous cells and regarding the structure it has proper chemical residence which has remained as a difficulty. The researchers have presented various solutions for solving the problem of selectability. For example Mark. A. Green et al., has illustrated that folate receptors and all the other compositions containing these receptors for therapeutic purposes can be applied according to US2011/0028714A1.
Other researchers have proposed the application of superficialized modified liposome with immune system deceiver compositions like PEG with different molecular weights as mentioned in EP 87311040.7. The other suggestions include the application of methods based on gene, antigen and antibody. A new solution in this regard is the application of the strategy of food supplements. In fact considering the nature of BNCT method i.e. explosion at the cell dimension level as the result of collision of low-energy thermal neutrons with the compositions containing plenty/sufficient amount of 10B aggregated in tumor cells, a type of cancerous cells can be deceived through cell nutrition mechanisms. So the cell will swallow a drug tumor cell or compositions containing the high levels of 10-Boron content which is bonded with a food composition. By this strategy, firstly the cell tends to bring much more drug containing high levels of 10-Boron into itself and secondly the retention time in tumor cell will increase. The other property of this strategy is that the food supplement compositions can be used in the production of the drug (in this case, the problem of toxicity has been solved automatically). The compositions containing Boron can be found in the bacterial antibiotics such as borophycin, boromycin, aplasmocyn, tarerolon.
Although the currently available methods for treating the tumors are able to satisfy a few needs of the human community, solving this global dilemma remained as an unresolved puzzle. Usage of the chemical drugs, radioactive and radiotherapy applications are of the common methods used for treating cancer. However, not only those methods are not sufficient, but also there is a long way that has to be passed by them. Using the method of Boron Neutron Capture Therapy (BNCT) with 10B-enriched drug is a novel method in treating the cancerous tumors. The Boron Neutron Capture Therapy (BNCT) has been developed in twentieth century with the growth of technology. Several studies have been carried out in the field of development of necessary instruments and 10B-supplier drugs and also the quality and amount of this drug. Hence there is a need to develop a composition for an effective and successful treatment of cancer using the Boron Neutron Capture Therapy (BNCT).
The above mentioned shortcomings, disadvantages and problems are addressed herein and which will be understood by reading and studying the following specification.